Improved Outcomes in Eosinophilic Esophagitis with Higher Medication Possession Ratio.

Eosinophilic esophagitis (EoE) disease activity can be caused by treatment non-adherence. Medication possession ratio (MPR) is an established metric of medication adherence. A higher MPR correlates with better outcomes in several chronic diseases, but MPR has not been investigated with respect to EoE. A retrospective cohort study was performed using an established EoE registry for the years 2005 to 2020. Treatment periods were identified, MPRs were calculated, and medical records were assessed for histologic remission (<15 eos/hpf), dysphagia, food impaction, stricture occurrence, and esophageal dilation that corresponded to each treatment period. In total, 275 treatment periods were included for analysis. The MPR in the histologic remission treatment period group was 0.91 (IQR 0.63-1) vs. 0.63 (IQR 0.31-0.95) for the non-remission treatment period group (p < 0.001). The optimal MPR cut-point for histologic remission was 0.7 (Sen 0.66, Spec 0.62, AUC 0.63). With MPRs ≥ 0.7, there were significantly increased odds of histologic remission (odds ratio 3.05, 95% confidence interval 1.79-5.30) and significantly decreased odds of dysphagia (OR 0.27, 95% CI 0.15-0.45), food impaction (OR 0.26, 95% CI 0.11-0.55), stricture occurrence (OR 0.52 95% CI 0.29-0.92), and esophageal dilation (OR 0.29, 95% CI 0.15-0.54). Assessing MPR before repeating an esophagogastroduodenoscopy may decrease unnecessary procedures in the clinical management of eosinophilic esophagitis.

Gastrointestinal Ostomies in Children: A Primer for the Pediatrician.

Despite the advancement of medical therapies in the care of the preterm neonate, in the management of short bowel syndrome and the control of pediatric inflammatory bowel disease, the need to create fecal ostomies remains a common, advantageous treatment option for many medically complex children.

Marching Band Injuries in Children Presenting to Emergency Departments in the United States, 2012-2021: A Trebling Tale.

Marching band is both a sport and a performance art. Organized athletics like American football, soccer, and cheerleading all have established epidemiologic trends of injury, including stigmata from head trauma. Despite the potential for mild to severe injury, there is a paucity of data on marching band-related morbidity. We examined the National Electronic Injury Surveillance System from 2012 to 2021 to describe demographic information and injury patterns. There were an estimated 20 335 marching band injuries (95% confidence interval: 12 892-27 777). The majority of injuries occurred in females (70%), and those aged 14 to 18 years (85%). Fifty percent of all injuries occurred in the lower extremity, and soft tissue injuries were the most frequently observed diagnosis (49%). Mild traumatic brain injury accounted for 6% of all injuries. Of marching band injury, 98% did not require escalation of care. Based on these findings, we suggest targeted public health intervention by sports medicine teams.

Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments.

Introduction: Q fever, caused by the intracellular bacterium Coxiella burnetii, is considered an occupational and biodefense hazard and can result in debilitating long-term complications. While natural infection and vaccination induce humoral and cellular immune responses, the exact nature of cellular immune responses to C. burnetii is incompletely understood. The current study seeks to investigate more deeply the nature of long-term cellular recall responses in naturally exposed individuals by both cytokine release assessment and cytometry profiling. Methods: Individuals exposed during the 2007-2010 Dutch Q fever outbreak were grouped in 2015, based on a C. burnetii-specific IFNγ release assay (IGRA), serological status, and self-reported clinical symptoms during initial infection, into asymptomatic IGRA-negative/seronegative controls, and three IGRA-positive groups (seronegative/asymptomatic; seropositive/asymptomatic and seropositive/symptomatic). Recall responses following in vitro re-stimulation with heat-inactivated C. burnetii in whole blood, were assessed in 2016/2017 by cytokine release assays (n=55) and flow cytometry (n=36), and in blood mononuclear cells by mass cytometry (n=36). Results: Cytokine release analysis showed significantly elevated IL-2 responses in all seropositive individuals and elevated IL-1ß responses in those recovered from symptomatic infection. Comparative flow cytometry analysis revealed significantly increased IFNγ, TNFα and IL-2 recall responses by CD4 T cells and higher IL-6 production by monocytes from symptomatic, IGRA-positive/seropositive individuals compared to controls. Mass cytometry profiling and unsupervised clustering analysis confirmed recall responses in seropositive individuals by two activated CD4 T cell subsets, one characterized by a strong Th1 cytokine profile (IFNγ+IL-2+TNFα+), and identified C. burnetii-specific activation of CD8 T cells in all IGRA-positive groups. Remarkably, increased C. burnetii-specific responses in IGRA-positive individuals were also observed in three innate cell subpopulations: one characterized by an IFNγ+IL-2+TNFα+ Th1 cytokine profile and lack of canonical marker expression, and two IL-1ß-, IL-6- and IL-8-producing CD14+ monocyte subsets that could be the drivers of elevated secretion of innate cytokines in pre-exposed individuals. Discussion: These data highlight that there are long-term increased responses to C. burnetii in both adaptive and innate cellular compartments, the latter being indicative of trained immunity. These findings warrant future studies into the protective role of these innate responses and may inform future Q fever vaccine design.

Autoimmune gastritis as an unexpected cause of diarrhea in a young adult with type I diabetes: a case report.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a lifelong diagnosis that involves immune-mediated damage of pancreatic beta cells and subsequent hyperglycemia, manifesting as: polyuria, polydipsia, polyphagia, and weight loss. Treatment of type 1 diabetes centers on insulin administration to replace or supplement the body's own insulin with the goal of achieving euglycemia and preventing or minimizing complications. Patients with T1DM are at risk for developing other autoimmune conditions, most commonly thyroid or celiac disease. CASE PRESENTATION: A 20-year-old African American female with T1DM was referred by her endocrinologist to pediatric gastroenterology for 2 months of nocturnal, non-bloody diarrhea, left lower quadrant pain, and nausea; she was also being followed by neurology for complaints of lower extremity paresthesias and pain. The patient's initial lab-workup was remarkable for a low total Immunoglobulin A (IgA) level of < 6.7 mg/dL. As IgA deficiency is associated with an increased risk of celiac disease, the patient underwent upper and lower endoscopy, which was grossly unremarkable; however, histology revealed a pattern consistent with autoimmune gastritis. Subsequent serum evaluation was remarkable for an elevated fasting gastrin level and an elevated parietal cell antibody level without macrocytic anemia, iron deficiency, or vitamin B12 depletion. The patient was diagnosed with autoimmune gastritis (AIG) and subsequently initiated on parenteral B12 supplementation therapy with improvement in her neurologic and gastrointestinal symptoms. CONCLUSION: This case illustrates the importance of recognition of red flag findings in a patient with known autoimmune disease. Following well-established health maintenance recommendations for individuals with T1DM ensures that common comorbidities will be detected. Autoimmune gastritis, while a rarer pathology in the pediatric population, deserves consideration in patients with pre-existing autoimmune conditions and new gastrointestinal or neurologic symptoms, as AIG can be associated with poor outcomes and risk of malignancy. Initial lab findings associated with an eventual diagnosis of AIG typically include anemia, iron deficiency, or Vitamin B12 deficiency. However, as demonstrated in this case, symptoms of AIG can rarely present before anemia or Vitamin B12 deficiency develops. To prevent permanent neurological damage, parenteral Vitamin B12 therapy must be considered even in the absence of Vitamin B12 deficiency, especially in those patients already experiencing neurological symptoms.

Gastrointestinal Bleeding in the Neonate: Updates on Diagnostics, Therapeutics, and Management.

Gastrointestinal bleeding (GIB) is a relatively uncommon presentation in the NICU. GIB in neonates includes a broad spectrum of disease morbidity, from minor reflux symptoms and growth failure to severe, clinically significant anemia requiring critical care resuscitation. Over the last several years, multiple diagnostic tools including fecal calprotectin and bedside ultrasonography have emerged and demonstrated utility in the early recognition of sources for GIB in neonates. Further evidence has continued to show that traditional medical therapy with intravenous proton pump inhibitors is well-tolerated, and that upper endoscopy has limited diagnostic and therapeutic value. Finally, additional research and quality improvement investigations are warranted to determine how best to prevent, recognize, and manage GIB in critical neonates.

B cell-dependent subtypes and treatment-based immune correlates to survival in stage 3 and 4 lung adenocarcinomas.

Lung cancer is the leading cause of cancer-related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non-small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late-stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA-Seq) with deconvolution of RNA-Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B-cell rich patient group had increased expression of CXCL13 and greater abundance of PD1+ CD8 T cells. The presence of B cells and PD1+ CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA-Seq datasets. As previously described by others, pre-treatment expression of intratumoral 12-chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre-treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non-ICI treatments.

Selective Bcl-2 inhibition promotes hematopoietic chimerism and allograft tolerance without myelosuppression in nonhuman primates.

Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs. To date, this has been achievable only by nonselective treatments such as irradiation or chemotherapeutic drugs. An approach that is capable of more selectively depleting host HSCs is needed to widen the clinical application of HSCT. Here, we show in a clinically relevant nonhuman primate model that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted hematopoietic chimerism and renal allograft tolerance after partial deletion of HSCs and effective peripheral lymphocyte deletion while preserving myeloid cells and regulatory T cells. Although Bcl-2 inhibition alone was insufficient to induce hematopoietic chimerism, the addition of a Bcl-2 inhibitor resulted in promotion of hematopoietic chimerism and renal allograft tolerance despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a promising approach to induce hematopoietic chimerism without myelosuppression and has the potential to render HSCT more feasible for a variety of clinical indications.

Development and Implementation of DIGEST: The Digital Interactive Gastroenterology Education Suite for Trainees.

INTRODUCTION: Clinical clerkship curricula should exist to provide rotating learners on subspecialty rotations with consistent exposure to specific topics geared toward the discipline of interest, such as pediatric gastroenterology (GI). We aim to describe our experience developing and implementing DIGEST: the Digital Interactive Gastroenterology Education Suite for Trainees, a novel, online GI curriculum delivered to virtual, rotating learners during the coronavirus (COVID-19) pandemic stay-at-home order. MATERIALS AND METHODS: A general needs assessment in 2019 identified a lack of standardized educational experience amongst the rotating learners on pediatric GI service. The COVID-19 pandemic compelled us to transition our curriculum from our institution's secure share drive to the GOOGLE classroom. A program evaluation was undertaken and included learner responses to content and confidence questionnaires and a health care professions education (HPE) expert's response to a course quality assessment rubric. RESULTS: Feasibility-the final DIGEST product was free of charge to create but incurred direct and indirect costs of time and training on behalf of the authors. Acceptance-7 possible learners participated and responded to the questionnaires (100% response rate). Learners reported a superior learning experience and increased confidence with DIGEST. An HPE expert reported that the course design of DIGEST met or exceeded expectations in all categories. CONCLUSIONS: DIGEST is a novel pediatric GI curriculum for rotating learners that could be rapidly deployed, or adapted, for a wide range of clinical disciplines within the Military Health System.

Development and assessment of a low literacy, pictographic asthma action plan with clinical automation to enhance guideline-concordant care for children with asthma.

OBJECTIVE: Asthma is characterized by reversible pulmonary symptoms, frequent hospitalizations, poor quality of life, and varied treatment. Parents with low health literacy (HL) is linked to poor asthma outcomes in children. Recent practice updates recommended inhaled corticosteroids for the management of persistent asthma, but guideline-concordant care is suboptimal. Our aim was to develop and assess an Asthma Action Plan (AAP) that could serve as an individualized plan for low HL families and facilitate guideline-concordant care for clinicians. METHODS: We followed the National Institute of Health 5-step "Clear & Simple" approach to develop the Uniformed Services AAP. Our AAP included symptom pictographs (dyspnea, cough, sleep, activity) and guideline-concordant clinical automation tools. Caregivers assessed the pictograms for validity (transparency of ≥ 85%; translucency score ≥ 5; and ≥ 85% recall). Readability was assessed using 7 formulas. (<6th Grade was acceptable). Comprehensibility, design quality, and usefulness was assessed by caregivers using the Consumer Information Rating Form (CIRF) (>80% was acceptable). Understandability and actionability was assessed by medical librarians using the Patient Education Materials Assessment Tool-Printable (>80% was acceptable). Suitability was assessed by clinicians using the modified Suitability Assessment of Materials (SAM) instrument (>70% was superior). RESULTS: All 12 pictograms were validated (N = 118 respondents). Readability demonstrated a 4th grade level. Overall CIRF percentile score = 80.4%. Understandability and Actionability = 100%. Suitability score = 75%. CONCLUSIONS: Our AAP was formally endorsed by the Allergy & Asthma Network. The Uniformed Services AAP is a novel tool with embedded clinical automation that can address low HL and enhance guideline-concordant care.

The Uniformed Services Constipation Action Plan: An Effective Tool for the Management of Children with Functional Constipation.

OBJECTIVE: To implement and to evaluate the effectiveness of the Uniformed Services Constipation Action Plan (USCAP) in our gastroenterology clinic for children with functional constipation. STUDY DESIGN: This implementation science study included toilet-trained subjects aged 4 years and older who met the Rome IV criteria for functional constipation. Children were block randomized to receive either the USCAP or control. All clinic functional constipation plans recommended subjects continue pharmacotherapy for 4 months. Endpoints measured were clinical outcomes (resolution of functional constipation and achievement of a Pediatric Bristol Stool Form Scale [PBSFS] score of 3 or 4), patient-related outcomes (health-related quality of life [HRQoL] total scale score), and health confidence outcomes (Health Confidence Score [HCS]). RESULTS: Fifty-seven treatment group subjects (44%) received a USCAP (52% male; mean age, 10.9 [4.9] years) compared with 73 controls (56%; 48% male; mean age,10.9 [5.3] years). A PBSFS score of 3 or 4 was achieved by 77% of the treatment group compared with 59% of controls (P = .03). Subjects from the treatment group were more likely than the controls to endorse adherence to the 4-month course of pharmacotherapy (P < .001). Subjects who received a USCAP had greater improvements in HRQoL total scale score by the end of the project (P = .04). CONCLUSIONS: The USCAP is a simple, inexpensive tool that has the potential to improve global outcomes for functional constipation in children and should be recommended as standard clinical practice.

Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo.

As severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evolves to escape natural antibodies, it also loses sensitivity to therapeutic antibody drugs. By contrast, evolution selects for binding to ACE2, the cell-surface receptor required for SARS-CoV-2 infection. Consistent with this, we find that an ACE2 decoy neutralizes antibody-resistant variants, including Omicron, with no loss in potency. To identify design features necessary for in vivo activity, we compare several enzymatically inactive, Fc effector-silenced ACE2-Fc decoys. Inclusion of the ACE2 collectrin-like domain not only improves affinity for the S protein but also unexpectedly extends serum half-life and is necessary to reduce disease severity and viral titer in Syrian hamsters. Fc effector function is not required. The activity of ACE2 decoy receptors is due, in part, to their ability to trigger an irreversible structural change in the viral S protein. Our studies provide a new understanding of how ACE2 decoys function and support their development as therapeutics to treat ACE2-dependent coronaviruses.

The Impact of the COVID-19 Pandemic on Foreign Body Ingestion Trends in Children: A Comparison of the Pre-Pandemic Period to 2020.

Foreign body ingestion (FBI) among children is associated with morbidity and mortality. We used the National Electronic Injury Surveillance System to compare FBI trends from 2017-2019 to 2020 during the spread of SARS-CoV-2. The pandemic and associated stay-at-home orders were associated with uptrends in button battery and magnet ingestions but unchanged total FBI trends.

Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes.

Cellular deconvolution algorithms virtually reconstruct tissue composition by analyzing the gene expression of complex tissues. We present the decision tree machine learning algorithm, Kassandra, trained on a broad collection of >9,400 tissue and blood sorted cell RNA profiles incorporated into millions of artificial transcriptomes to accurately reconstruct the tumor microenvironment (TME). Bioinformatics correction for technical and biological variability, aberrant cancer cell expression inclusion, and accurate quantification and normalization of transcript expression increased Kassandra stability and robustness. Performance was validated on 4,000 H&E slides and 1,000 tissues by comparison with cytometric, immunohistochemical, or single-cell RNA-seq measurements. Kassandra accurately deconvolved TME elements, showing the role of these populations in tumor pathogenesis and other biological processes. Digital TME reconstruction revealed that the presence of PD-1-positive CD8+ T cells strongly correlated with immunotherapy response and increased the predictive potential of established biomarkers, indicating that Kassandra could potentially be utilized in future clinical applications.

Clinical action plans make a difference at point-of-care.

PURPOSE OF REVIEW: The purpose of this review is to provide an update to and roadmap for the practical implementation of various point-of-care clinical action plans for primary care providers. RECENT FINDINGS: Clinical action plans were first developed to address unmet, home preventive needs for the management of asthma. Over the past 10 years, the advancement of mobile health technologies, the recognition of at-risk populations, and the development of evidence-based concepts to guide the creation of patient education tools have expanded the implementation of clinical action plans for many diagnoses (e.g., functional constipation, atopic dermatitis, and headache migraines). Poor patient-related clinical outcomes have been linked with low health literacy for many chronic diseases of childhood. This has served as a call to action to improve patient education. Clinical action plans address this gap by facilitating superior knowledge transfer from the medical team in the clinic to the patient/caregiver. The use of clinical action plans can serve as clinical decision support tools for the medical team and has been demonstrated to improve patient adherence to complex therapy regimens. SUMMARY: Clinical action plans have the potential to improve disease-related self-management confidence, increase pharmacotherapy adherence, and enhance guideline-concordant care. These clinical decision support tools are safe, inexpensive, and represent an advancement in the high-value care model in pediatric medicine.

Evaluation of a Human T Cell-Targeted Multi-Epitope Vaccine for Q Fever in Animal Models of Coxiella burnetii Immunity.

T cell-mediated immunity plays a central role in the control and clearance of intracellular Coxiella burnetii infection, which can cause Q fever. Therefore, we aimed to develop a novel T cell-targeted vaccine that induces pathogen-specific cell-mediated immunity to protect against Q fever in humans while avoiding the reactogenicity of the current inactivated whole cell vaccine. Human HLA class II T cell epitopes from C. burnetii were previously identified and selected by immunoinformatic predictions of HLA binding, conservation in multiple C. burnetii isolates, and low potential for cross-reactivity with the human proteome or microbiome. Epitopes were selected for vaccine inclusion based on long-lived human T cell recall responses to corresponding peptides in individuals that had been naturally exposed to the bacterium during a 2007-2010 Q fever outbreak in the Netherlands. Multiple viral vector-based candidate vaccines were generated that express concatemers of selected epitope sequences arranged to minimize potential junctional neo-epitopes. The vaccine candidates caused no antigen-specific reactogenicity in a sensitized guinea pig model. A subset of the vaccine epitope peptides elicited antigenic recall responses in splenocytes from C57BL/6 mice previously infected with C. burnetii. However, immunogenicity of the vaccine candidates in C57BL/6 mice was dominated by a single epitope and this was insufficient to confer protection against an infection challenge, highlighting the limitations of assessing human-targeted vaccine candidates in murine models. The viral vector-based vaccine candidates induced antigen-specific T cell responses to a broader array of epitopes in cynomolgus macaques, establishing a foundation for future vaccine efficacy studies in this large animal model of C. burnetii infection.